Biodegradable self-expanding prosthesis

ABSTRACT

Disclosed herein is a biodegradable prosthesis that includes a first end, a second end, and an elongate tubular body with a lumen therethrough. The prosthesis can have a first layer comprising a set of flexible interbraided bioabsorbable filaments, and optionally a set of flexible interbraided metallic filaments. Also, the prosthesis can have a second layer comprising a porous thermoplastic material that can be either an outer layer or an inner layer relative to the first layer. The prosthesis can include other features including branch apertures, folded portions, and attachment mechanisms for the first and second layers.

This application claims priority under 35 U.S.C. §120 as a continuationof U.S. patent application Ser. No. 12/503,762 filed on Jul. 15, 2009and currently pending, which is in turn a continuation-in-partapplication of U.S. patent application Ser. No. 11/972,406 filed on Jan.10, 2008 and currently pending. Each of the aforementioned priorityapplications are hereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates generally to implantable, radiallyexpandable medical prostheses, often referred to as stents.

DESCRIPTION OF THE RELATED ART

The present invention relates generally to implantable, radiallyexpandable medical prostheses which are frequently referred to asstents. In particular, some embodiments of the invention include abioabsorbable self-expanding stent with a controlled-mass release anddrug layer.

Atherosclerotic disease, for example, causes localized occlusion of theblood vessels resulting from the build-up of plaque. As the depositsincrease in size, they reduce the diameter of the arteries and impedeblood circulation.

Restenosis is the reclosure of a peripheral or coronary artery followingtrauma to that artery caused by efforts to open a stenosed portion ofthe artery, such as, for example, by balloon dilation, ablation,atherectomy or laser treatment of the artery. For these angioplastyprocedures, restenosis occurs at a rate of about 20-50% depending on thedefinition, vessel location, lesion length and a number of othermorphological and clinical variables. Restenosis is believed to be anatural healing reaction to the injury of the arterial wall that iscaused by angioplasty procedures. The healing reaction begins with thethrombotic mechanism at the site of the injury. The final result of thecomplex steps of the healing process can be intimal hyperplasia, theuncontrolled migration and proliferation of medial smooth muscle cells,combined with their extracellular matrix production, until the artery isagain stenosed or occluded.

Self-expanding medical prostheses frequently referred to as stents arewell known and commercially available. They are; for example, disclosedgenerally in U.S. Pat. No. 4,655,771 to Wallsten, U.S. Pat. No.5,061,275 to Wallsten et al., and Hachtmann et al., U.S. Pat. No.5,645,559, which are all hereby incorporated by reference in theirentirety. Devices are used within body vessels of humans for a varietyof medical applications. Examples include intravascular stents fortreating stenoses, stents for maintaining openings in the urinary,biliary, tracheobronchial, esophageal, and renal tracts, and vena cavafilters.

A delivery device which retains the stent in its compressed state isused to deliver the stent to a treatment site through vessels in thebody. The flexible nature and reduced radius of the compressed stentenables it to be delivered through relatively small and curved vessels.In percutaneous transluminal angioplasty, an implantable endoprosthesisis introduced through a small percutaneous puncture site, airway, orport and is passed through various body vessels to the treatment site.After the stent is positioned at the treatment site, the delivery deviceis actuated to release the stent, thereby allowing the stent toself-expand within the body vessel. The delivery device is then detachedfrom the stent and removed from the patient. The stent remains in thevessel at the treatment site as an implant.

Stents must exhibit a relatively high degree of biocompatibility sincethey are implanted in the body. An endoprosthesis may be delivered intoa body lumen on or within a surgical delivery system such as deliverydevices shown in U.S. Pat. Nos. 4,954,126 and 5,026,377, which arehereby incorporated by reference in their entirety. Delivery devicesthat can be used for the present invention include U.S. Pat. Nos.4,954,126 and 5,026,377, which are hereby incorporated by reference intheir entirety. Suitable materials for use with such delivery devicesare described in U.S. Pat. No. 6,042,578, hereby incorporated byreference in its entirety.

Commonly used materials for known stent filaments include Elgiloy® andPhynox® metal spring alloys. Other metallic materials than can be usedfor self-expanding stent filaments are 316 LVM stainless steel, MP35Nalloy, and superelastic Nitinol nickel-titanium alloy including shapememory and temperature sensitive types. Another self-expanding stent,available from Schneider (USA) Inc. of Minneapolis, Minn., has aradiopaque clad composite structure such as shown in U.S. Pat. No.5,630,840 to Mayer. Self-expanding stents can be made of a TitaniumAlloy as described in U.S. Pat. No. 6,042,578, hereby incorporated byreference in its entirety.

The strength and modulus of elasticity of the filaments forming thestents are also important characteristics. Elgiloy®, Phynox®, MP35N andstainless steel are all high strength and high modulus metals. Nitinolhas relatively low strength and modulus.

The implantation of an intraluminal stent will preferably cause agenerally reduced amount of acute and chronic trauma to the luminal wallwhile performing its function. A stent that applies a gentle radialforce against the wall and that is compliant and flexible with lumenmovements is preferred for use in diseased, weakened, or brittle lumens.The stent will preferably be capable of withstanding radially occlusivepressure from tumors, plaque, and luminal recoil and remodeling.

Pharmacologic attempts have been made to reduce the rate of restenosis.These attempts have generally dealt with the systemic delivery of drugsvia oral, intravascular, or intramuscular introduction. Little, if anysuccess has been achieved with this systemic approach.

For drug delivery, it has been recognized for a long period of time thatpills and injections may not be the best mode of administration. It isvery difficult with these types of administration to obtain constantdrug delivery. Patient noncompliance with instructions is also aproblem. Through repeated doses, these drugs often cycle throughconcentration peaks and valleys, resulting in time periods of toxicityand ineffectiveness. Thus, localized drug treatment is warranted.

There remains a continuing need for self-expanding stents withparticular characteristics for use in various medical indications.Stents are needed for implantation in an ever growing list of vessels inthe body. Different physiological environments are encountered and it isrecognized that there is no universally acceptable set of stentcharacteristics.

A need exists for a stent which has self expanding characteristics, butwhich is bioabsorbable, as well as a controlled-mass release and druglayer. A surgical implant such as a stent endoprosthesis is preferablymade of a non-toxic, biocompatible material in order to minimize theforeign-body response of the host tissue. The implant also should havesufficient structural strength, biostability, size, and durability towithstand the conditions and confinement in a body lumen. Some importantlimitations of vascular stents, especially peripheral stents todayinclude the high restenosis rate, even with drug-eluting stents.Possible non-limiting reasons for stent failure today include (1)continuous chronic over-expansion (excessive chronic outward forcesleading to chronic injury), (2) strut fracture leading to uncoveredareas and injury; (3) irreversible bending of the prosthesis as aconsequence of excessive torsion forces; and (4) poor vascularconformability. A need exists for stents that improve on some or all ofthese limitations.

All documents cited herein, including the foregoing, are incorporatedherein by reference in their entireties for all purposes.

SUMMARY OF THE INVENTION

There is provided in accordance with one aspect of the presentinvention, a hybrid biodegradable prosthesis. The prosthesis comprises afirst end, a second end, and an elongate tubular body with a lumentherethrough. An outer layer comprises a drug delivery element. In oneembodiment, the drug delivery element comprises polyphosphoestermicrospheres. The middle layer may comprise a plurality of flexibleinterbraided bioabsorbable filaments. An inner layer comprises a porousthermoplastic material. The inner layer provides a conduit for bloodflow, and is configured to integrate into the vascular tissue. Thus, theprosthesis is a hybrid device, in which a first portion is absorbable orerodable over time, and a second portion is incorporated by cellularin-growth into the vascular intima.

In accordance with another aspect of the present invention there isprovided a method of treating a patient. The method comprises the stepsof providing a coaxial delivery system, including a catheter, loadedwith a stent as described above. The catheter is advanced to a treatmentsite and the stent is deployed at the treatment site.

In accordance with a further aspect of the present invention, there isprovided a medical system. This system comprises a catheter, having aradially expandable hybrid stent loaded thereon having an absorbablecomponent and a permanent component.

An outer diameter at the first end of the prosthesis can be larger thana smaller outer diameter at a mid-point on the prosthesis axiallydisplaced from the first end of the prosthesis. The larger diameter maybe at least about 0.005 inches or more, or between about 5-9% greater insome embodiments than the smaller diameter. The outer layer may includeany drug or biologically active substance depending on the desiredclinical result, such as paclitaxel, rapamycin, zotarolimus, ortacrolimus.

The middle layer can be annealed to form various shapes and geometries.The bioabsorbable filaments can comprise a material selected from thegroup consisting of polylactide, poly-L-lactide (PLLA), poly-D-lactide(PDLA), polyglycolide (PGA), polydioxanone, polycaprolactone,polygluconate, polylactic acid-polyethylene oxide copolymers, modifiedcellulose, collagen, poly(hydroxybutyrate), polyanhydride,polyphosphoester; poly(amino acids), and poly(alpha-hydroxy acid). Insome embodiments, the first end and/or the second end of the prosthesiscomprise a drug delivery reservoir. In some embodiments, at least thefirst end or the second end of the stent is flared and folded to provideenhanced radial support. The stent may include at least one radioopaquemarker element. The prosthesis can further include a second drugdelivery element on an inner surface of the inner layer of the stent.

Also disclosed herein is a method of forming a vascular prosthesis,comprising: the steps of providing a first tubular body comprising aporous thermoplastic material; providing a second tubular bodycomprising a plurality of bioabsorbable filaments woven helically alonga central axis of the second tubular body, the second tubular bodyhaving a outer diameter greater than that of the first tubular body;annealing the first tubular body to the second tubular body; andapplying a coating layer to an outer surface of the second tubular body.In some embodiments, a crossing angle of the helically wovenbioabsorbable filaments is between about 90 to 160 degrees, 120 and 160degrees, or 90 to 140 degrees. In some embodiments, applying a coatinglayer involves one of spraying, dipping, or printing. The coating can bea drug coating.

Another aspect of the invention involves a biodegradable prosthesis,having a first end, a second end, and an elongate tubular body defininga sidewall with a lumen therethrough; a first layer comprising a set offlexible interbraided bioabsorbable filaments arranged in a helicalpattern; and a second layer comprising a porous thermoplastic material,which can be ePTFE. The first layer and/or second layer can includefolded portion(s) on a first end, such as a proximal end, and/or asecond end, such as a distal end. The folded portions can be configuredto remain folded while the prosthesis is implanted within a body lumen.The first layer could be either an outer or inner layer with respect tothe second layer. The prosthesis could include 1, 2, 3, 4, 5, 6, or moreradioopaque marker elements, which can be located anywhere on theprosthesis, such as secured within the folded layers of one or morefolded portions of the prosthesis. The radioopaque marker element may bemade of any appropriate metal or metallic material, such as atitanium-iridium alloy. The prosthesis can also include 1, 2, or morebranch apertures disposed on the sidewall of the tubular body andconfigured to promote fluid flow into one or more side-branch vessels,such as at their ostia. In some embodiments, an outer diameter at thefirst end of the prosthesis is larger than an outer diameter at amid-point on the prosthesis axially displaced from the first end of theprosthesis, such as at least 0.005 inches larger in some embodiments.The first layer and the second layer can be adhered, sutured, orotherwise attached together at various locations, such as within one ormore folded portions of the prosthesis. A drug delivery characteristic,such as paclitaxel, rapamycin, zotarolimus, and tacrolimus for examplecan be operably attached to the first layer of the prosthesis in someembodiments. The first layer can be annealed to the second layer.

In another aspect, disclosed herein is an intraluminal prosthesis thathas a first end, a second end, and an elongate tubular body within alumen therethrough. The prosthesis can include a first layer withflexible interbraided filaments that can be helically woven in somecases. The first group of filaments can include a biodegradablematerial. The second group of filaments can comprise a metallicmaterial. The prosthesis can include any number of filaments, such asbetween 10-36 filaments in some embodiments. The filaments that includea metallic material can include no more than about 70%, 60%, 50%, 40%,30%, 25%, 20%, 10% or less of the total number of filaments. A secondlayer of a porous thermoplastic material can be operably attached to thefirst layer, as either an outer layer or an inner layer with respect tothe first layer.

A method of forming a vascular prosthesis is also disclosed, includingthe steps of providing a first tubular body comprising a porousthermoplastic material; providing a second tubular body comprising aplurality of bioabsorbable filaments woven helically along a centralaxis of the second tubular body; folding a portion of the first tubularbody over a portion of the second tubular body; and annealing the firsttubular body to the second tubular body. The method can also include thestep of applying a coating layer to an outer surface of the secondtubular body. The crossing angle of the helically woven bioabsorbablefilaments can be from about 90 to about 140 degrees in some embodiments.Applying a coating layer, such as a drug coating can involve spraying,dipping, or microprinting.

In another embodiment, a method of treating a patient can includeproviding a coaxial delivery system, including a catheter loaded with aprosthesis as disclosed elsewhere herein, and deploying the prosthesisin the patient at a treatment site. In some embodiments, the coaxialdelivery system is configured to house multiple stents for deliveryduring a single procedure, such as at least 2, 3, 4, 5, or more stents.

Also disclosed herein is a medical system that includes a catheter and aradially expandable stent as described elsewhere herein, carried by adistal section of the catheter. The system can also include a lubriciouscoating on the catheter.

Further features and advantages of the present invention will becomeapparent to those of skill in the art in view of the detaileddescription of preferred embodiments which follows, when consideredtogether with the attached drawings and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically illustrates in partial cut away view varioussections of a multilayer self-expanding prosthesis according to oneembodiment of the invention.

FIG. 2A illustrates a stent with enlarged, flared, tapered proximal anddistal ends, according to one embodiment of the invention.

FIG. 2B is a close-up side view of a cross-section of the stent endsshown of FIG. 2A that illustrates flared ends of the stent. The innersynthetic membrane layer may be compressed, laminated, and/or bonded tothe braided bioabsorbable layer, such as through induction of heat andcompression.

FIG. 2C schematically illustrates a plurality of tubular bodies in whichlayers 2010 and 2030 can be annealed together to create a stent,according to one embodiment of the invention. Layer 2020 can also becreated by spraying, dipping, and/or micro-printing coating processes.

FIGS. 3-4 illustrates in intermediate stent layer with biodegradableinterwound filaments, which can provide increased radial support for thestent, according to one embodiment of the invention.

FIG. 5 illustrates a cross-section of a polymeric filament.

FIG. 6 illustrates a schematic cut-away view of a woven filament layerwith a coated drug-release layer, according to one embodiment of theinvention.

FIG. 7 illustrates a stent with a non-circular acorn-shapedcross-section, according to one embodiment of the invention.

FIGS. 8-11 illustrate various folded stent configurations, according tosome embodiments of the invention.

FIGS. 11A-11B illustrate a schematic perspective view of a stent havingone, two, or more branch apertures, in accordance with some embodimentsof the invention.

FIG. 11C illustrates a schematic perspective view of a stent having sideorifices implanted in a main vessel with the side orifices providing aflow path into side vessels, in accordance with one embodiment of theinvention.

FIGS. 11D-11F illustrate cross-sectional views of various foldingpatterns of one or more layers of a stent, in accordance with someembodiments of the invention.

FIG. 11G illustrates a perspective view of a stent with folded endsegments, in accordance with one embodiment of the invention.

FIGS. 11H -11I illustrate schematic views of various suturing patternsover folded portions of the stent in order to secure multiple stentlayers together, in accordance with some embodiments of the invention.

FIG. 11J is a schematic view of a stent having a biodegradable wovenlayer, according to one embodiment of the invention.

FIG. 11K is a cross-sectional view of the stent of FIG. 11J through line11K-11K.

FIG. 11L is a schematic view of a stent having an outer biodegradablewoven layer and an inner porous membrane layer, according to oneembodiment of the invention.

FIG. 11M is a schematic view of a stent having an inner biodegradablewoven layer and an outer porous membrane layer, according to oneembodiment of the invention.

FIG. 11N is a cross-sectional view of the stent of FIG. 11M through line11N-11N.

FIG. 11O is a schematic view of a stent having a hybrid weave ofbiodegradable fibers and metallic fibers, according to one embodiment ofthe invention.

FIG. 11P is a cross-sectional view of the stent of FIG. 11O through line11P-11P.

FIGS. 12-20 illustrate various devices for delivery of a stent to a bodylumen, according to some embodiments of the invention.

FIGS. 21A-21C illustrate an alternative stent delivery system andvarious components, according to some embodiments of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention relates generally to a hybrid construct adaptedfor implantation in a living organism, such as a human. The constructincludes at least a first portion which is bioabsorbable, and maysupport a drug delivery characteristic. The bioabsorbable component maybe attached to a nonabsorbable or permanent component. Thus, followingimplantation in the body, the bioabsorbable component graduallydisappears, while the permanent component becomes attached to and/orintegrated within the adjacent tissue. The term ‘bioabsorbable’ is usedherein only to indicate a transient presence in the body, and to includeall mechanisms by which the implant or implant component may disappearover time, including dissolution, absorption, erosion or others.

The hybrid construct of the present invention will be describedprimarily herein in a tubular form, particularly adapted forimplantation within the cardiovascular system. It should be appreciatedthat the tubular form of the present invention may also be configuredfor implantation within other hollow organs or tubular structures withinthe body, such as the gastro intestinal tract including the stomach,esophagus, various portions of the intestine and colon. The tubularconstruct may alternatively be configured for positioning in theairways, such as the trachea, bronchial tubes, or other portions of thelung, and the sinus and nasal cavities. Alternative embodiments may beconfigured for implantation within the urethra, ureters, fallopiantubes, uterus, vagina, or elsewhere as will be appreciated by those ofskill in the art. Within the cardiovascular system, tubular embodimentsof the present invention may be configured for implantation within thecoronary vasculature, peripheral vasculature, and intracranialvasculature. Additional indications will be discussed below.

Nontubular embodiments of the present invention may be provided in theform of a multilayer patch, which may be utilized to span or repair anyof a variety of tissue defects, such as hernias, ulcerations,perforations, or other defects or injuries caused by surgery, traumaticinjury or disease states.

For example, the embodiment illustrated in FIG. 1 comprises at leastthree layers formed in a tubular configuration for intravascularimplantation. Although described below as discrete layers, it should beappreciated that the composition of each of the three layers may beinterwoven or intermingled with the adjacent layer or layers as will beappreciated by those of skill in the art in view of the descriptionherein.

Referring to FIG. 1, a structural intermediate support layer 201 maycomprise a woven braided helically wound or otherwise configured fabricor filament structure. The filament layer 201 may be absorbable as isdisclosed elsewhere herein. Preferably, the filament layer 201 isself-expandable from a reduced cross-sectional configuration such as fortransluminal navigation to a deployment site, to an enlargedcross-sectional configuration such as for lining a vessel. The filamentlayer 201 is sometimes referred to herein as the second or intermediatelayer.

Disposed concentrically within the central lumen defined by the secondlayer 201 is an inner first layer 200. The inner first layer 200comprises a thin membrane discussed in greater detail below. In certainembodiments, the membrane is provided with a microporous or macroporousstructure configured to permit cellular in-growth from the adjacentvascular wall, optimally of a nature sufficient to provide a viableneointimal lining on the inner, luminal surface of the implant.

The outermost or third layer 202 comprises a drug releasecharacteristic. The drug release characteristic may be provided in anyof a variety of ways, such as by inclusion of microspheres on thesurface of the construct, dipping, spraying or other coating operations,chemical and/or mechanical binder layers or tie layers or the like. Theouter layer 202 may thus reside within the interstitial spaces betweenthe adjacent filaments of the second layer 201 and/or radially outwardlydisposed with respect to the filaments of the second layer 201.Alternatively, the outer layer 202 may comprise a coating upon eachindividual filament, as is discussed below.

In general terms, the construct of the present invention is intended tobe transvascularly advanced to a treatment site and deployed such thatthe outer layer 202 is brought into contact with the intimal lining ofthe vessel, through the self-expanding characteristic created by thesecond layer 201 and potentially assisted by the first layer 200. Thispermits blood flow through the central lumen, while the drug deliverylayer is maintained against the vessel wall. The construct remains inposition while drug is eluted from the outer layer 202. In an absorbableembodiment, at least a first portion of the stent which may include thesecond layer 201 and an outer layer 202 may be absorbable or erodable atthe implantation site. At the same time, the intermediate tubular layer200 may be non-erodable. In this embodiment, after a desiredpredetermined period of time, the implant ceases to deliver drug fromthe outer layer 202, the second layer 201 and outer layer 202 graduallyare absorbed by the body, and cellular in-growth from the vessel wallenters the porous structure of the first layer 200, to provide a robustcellular lining on the luminal surface of the first layer 200. In thismanner, the tubular layer 200 is integrated into the vessel wall andthus becomes biologically “invisible” to blood flow through the vessel.

FIG. 1 schematically illustrates in a partial cut-away view varioussections of an embodiment of a self-expanding multi-layer prosthesis1000, or stent that is preferably at least partially bioresorbable insome embodiments. The prosthesis 1000 comprises multiple layers. A firstlayer 200 which is preferably the innermost layer, can be a membranemade of a biocompatible material such polyethylene, polyurethane,Teflon, or ePTFE with a thickness of about 0.001 to 0.010 inches,preferably between about 0.002 to 0.005 inches, and an inside diameterof between about 0.20 to 0.57 inches, such as about 0.267 +/−0.005inches in some embodiments. The first layer 200 is preferably porous(e.g., via pores 101), having a pore size of between about 0.05-1.5microns, such as between about 0.05 to 1 microns, or between about 0.1and 0.5 microns in some embodiments. Porous as used herein includestortuous pathways such as is present in the fibril and node structure ofePTFE. The average internodal distance could be between about 15-60micrometers in some embodiments, such as between about 30-50micrometers. The porosity could be, for example, between about 10-99%,such as between about 50-95% or about 80-90% in some embodiments. Insome embodiments, the water entry pressure of the layer could be betweenabout 5-15 psi, such as between about 6.5-9 psi. In some embodiments,the machine direction tensile strength of the layer could be at leastabout 1,000 psi, 2,000 psi, 4,000 psi, or more, with a transversedirection tensile strength of at least about 1,000 psi, 1,500 psi, 1,650psi, 1,800 psi, 2,000 psi, or more. The biocompatible membranous layer200 can be, in some embodiments, interwound radially to a second layer201 of bioabsorbable helically wound polymeric filaments 14, forexample, polylactic acid-polyethylene oxide copolymers, polydioxanone,polyglycolic acid, polylactic acid, polycaprolactone, polycarolactone,polygluconate, polyanhyride, polyaminoacids, and combinations thereof,as discussed in greater detail below.

The outer layer 202 preferably comprises a controlled drug releaseelement 102, which may be incorporated into polyphosphate estermicrospheres deposited on layer 201 in some embodiments. In someembodiments, the controlled drug release element layer may be depositedon either or both of the inner and outer surfaces of the biocompatiblelayer 200 and/or the polymeric filament layer 201. The drug may be anydrug known in the art. In some embodiments, the drug is animmunosuppressant or antiproliferative agent, such as paclitaxel(Taxol), rapamycin (Sirolimus), zotarolimus, or tacrolimus. In otherembodiments, the drug may be an anti-platelet agent such as heparin,hirudin, or enoxaparin, or any other drug or bioactive compounddepending on the desired clinical result.

Stent 1000 may also include one or more radioopaque marker elements 11as discussed in greater detail below.

To satisfy the clinical needs on drug-eluting stents, in terms ofproviding the effective concentration of bioactive active agents in atimely manner, some embodiments provide one or more pharmaceuticalagents which can be highly efficacious in controlling virtually all thebiological events leading to restenosis.

In some embodiments, the prosthesis has a cambered interior surface ofbetween about 10 to 20 degrees, similar to that disclosed in U.S. Pat.No. 5,551,954 to Buscemi et al, which is hereby incorporated byreference in its entirety.

Controlled release of a drug, via, for example, a bioabsorbable polymeroffers to maintain the drug level within the desired therapeutic rangefor the duration of the treatment. In the case of stents, the prosthesismaterials will maintain vessel support for weeks, months, or more oruntil incorporated into the vessel wall even with bioabsorbable,biodegradable polymer constructions. While the drug release layer isdepicted as the outermost layer, it can be alternatively present as aninner or intermediate layer. In some embodiments, multiple drug releaselayers may be present.

Several polymeric compounds that are known to be bioabsorbable andhypothetically have the ability to be drug impregnated may be useful inprosthesis formation herein. These compounds include: poly-l-lacticacid/polyglycolic acid, polyanhydride, and polyphosphate ester. A briefdescription of each is given below.

Poly-l-lactic acid/polyglycolic acid has been used for many years in thearea of bioabsorbable sutures. It is currently available in many forms,i.e., crystals, fibers, blocks, plates, etc. These compounds degradeinto non-toxic lactic and glycolic acids.

Another compound which could be used are the polyanhydrides. They arecurrently being used with several chemotherapy drugs for the treatmentof cancerous tumors. These drugs are compounded into the polymer whichis molded into a cube-like structure and surgically implanted at thetumor site.

In some embodiments, the drug delivery element includes a polyphosphateester. Polyphosphate ester is a compound such as that disclosed in U.S.Pat. Nos. 5,176,907; 5,194,581; and 5,656,765 issued to Leong which areincorporated herein by reference in their entirety. Similar to thepolyanhydrides, polyphosphate ester is suitable for drug delivery.Unlike the polyanhydrides, the polyphosphate esters have high molecularweights (600,000 MW average), yielding attractive mechanical properties.This high molecular weight leads to transparency, and film and fiberproperties. It has also been observed that the phosphorous-carbon-oxygenplasticizing effect, which lowers the glass transition temperature,makes the polymer desirable for fabrication. The highly hydrolyticallyreactive phosphorous ester bond, the favorable physical properties, andthe versatile chemical structure make the polyphosphate esters asuperior drug delivery system for a prosthesis. PPE microspheres mayalso be incorporated into the stent as disclosed in U.S. Pat. No.5,545,208 to Wolff et al., which is hereby incorporated by reference inits entirety.

The drug-eluting layer may be operably attached to the other layers ofthe prosthesis, for example, by spray-dipping, coating, annealing, orcovalently or noncovalent binding as known in the art.

Non-limiting examples of drugs that may be incorporated into theprosthesis described herein that can be used individually or indifferent combinations are discussed below.

Paclitaxel, is an antineoplastic compound which is used clinically incommercially available drug-eluting stents. This drug can also be usedas an anti-inflammatory agent with an exceptionally narrow therapeuticwindow beyond which it can be cytotoxic. In some embodiments, theprosthesis may include one drug delivery reservoir with paclitaxel andanother drug delivery reservoir with an antineoplastic agent, sometimesin combination with other drugs known for their anti-inflammatoryactivities (e.g., naproxen) and/or being immunosuppressant (e.g.,rapamycin).

Rapamycin is clinically used in commercially available drug-elutingstents. This drug is also used as an immunosuppressant having a widetherapeutic window. However, its use in drug-eluting stents in the priorart may not provide the optimum pharmacokinetics when released from anon-uniform coating. This invention also provides for use of rapamycinin combination with at least one additional bioactive agent, withdifferent pharmacological activity, such as in one or more drug deliveryreservoirs. Typical examples of these other agents include endothelialcell growth promoters (e.g., vascular endothelial growth factor or itspolypeptide functional analog), smooth muscle growth inhibitors, andantibiotics.

Antineoplastic agents, such as dactimycin, doxorubicin, mitomycin,mitoxantrone, and topotecan, also exhibit antibiotic activities. Thesecan be used individually or in combination with other drugs (that may beloaded in separate drug delivery reservoirs), particularly those knownto exhibit anti-inflammatory activity and/or promote endothelial cellgrowth.

Antineoplastic agents are also folate antagonists, such as methotrexate.The latter drug is also antimetabolite and immunosuppressant but can bean irritant. To mediate the latter effect, methotrexate can be used incombination with an anti-inflammatory drug and/or endothelial cellgrowth promoters, such as vascular endothelial growth factor (VEGF) orits polypeptide functional analog.

Anti-inflammatory drugs, which can be used alone or in combination withantineoplastic agents and/or immunosuppressants. Examples of theseanti-inflammatory drugs include (a) colchicine, which is also anantineoplastic compound that can be used to retard smooth muscle cellproliferation and can preferably be used in combination with anendothelial cell growth promoter, such as VEGF or its polypeptidefunctional analog; (b) the NSAID, indomethacin; (c) the NSAID,piroxicam, which may also be an immunosuppressant; and (d) thecorticosteroid, prednisone, which may also exhibit antineoplasticactivity.

Leflunamide, a member of the isoxazole class of drugs, exhibitsanti-inflammatory, antiproliferative, and immunosuppressive activities.This can be used alone or in combination with an endothelial cellpromoter.

Thalidomide is an anti-inflammatory drug that also exhibitsanti-angiogenic and immunosuppressive activities. This can be used aloneor in combination with an endothelial cell growth promoter.

Curcumin is an anti-inflammatory drug, which also exhibitsantiproliferative activities.

Mycophenolate mofetil is an immunosuppressant that is endowed withanti-inflammatory properties. This can be used alone or in combinationwith an endothelial cell promoter.

Methotrexate is an anti-inflammatory and immuno-regulatory drug. Itexhibits antiproliferative activity and can be used alone or incombination with an endothelial cell growth promoter, such as vascularendothelial growth factor or its polypeptide functional analog.

Dihydrofolate reductase is an anti-infective, antineoplastic, andanti-inflammatory agent. It can be used alone or in combination with anendothelial cell growth promoter.

Deferoxamine has been used extensively as chelation therapy iniron-loaded states and noted recently for its usefulness as anantiproliferative, anti-inflammatory, and immunosuppressive agent. Itcan be used alone or in combination with an endothelial cell growthpromoter.

Antibiotics produced by members of the bacterial genus Streptomyces,such as streptomycin-B, actinomycin-F1, and actinomycin-D, also exhibitantineoplastic and/or immunosuppressive activities.

Antineoplastics which are also antimetabolites, such as fludarabine andfluorouracil, can be used alone or in combination with ananti-inflammatory drug.

Growth factors such as endothelial or fibrous tissue growth factors,agonists or antagonists, or neurotrophic proteins, such as nerve growthfactor, can also be incorporated.

In some embodiments, tropomyosin along with troponin could be utilizedto regulate the shortening of the muscle protein filaments action andmyosin. In resting muscle fibers, tropomyosin is displaced from itsnormal binding groove by troponin.

In some embodiments regenerative cells such as adult stem cells,vascular endothelial cells, vascular smooth cells including but notlimited to myofibril including RNA (MIR) promotes cardiac myofibril geneexpression and is important for embryonic heart development. Othersimilar stem cells such as human embryonic stem cells from Geron (MenloPark, Calif.) can also be operably attached to one or more layers of thestent.

In some embodiments, the controlled drug release element comprisespolyphosphoester microspheres. Layers 200 and 201 of FIG. 1, in someembodiments, can be configured with a certain porosity meeting theAssociation for the Advancement of Medical Instrumentation (AAMI)standard for vascular graft applications to allow the device tointegrate into tissue at the vascular site. This feature would improvelodging within the vessels, as well as promotion of integration and cellgrowth through the sidewall of the permanent component(s) of the implantto embed the implant in the vascular wall at the treatment site.

FIG. 2A illustrates an embodiment of a prosthesis 108, shownschematically and not to scale, with enlarged, flared end portions 9.The outer drug delivery element and inner tubular membrane are not shownfor clarity. The enlarged end portions 9 are created as the ends offibers 12 from the biodegradable polymer layer (discussed below) runningaxially across the prosthesis 108 are secured at the distal and proximalend of the prosthesis at 9. As will be discussed, in some embodiments,fibers 12 can be interwoven in an over and under braided configurationintersecting at points such as 14 to form an open mesh or weaveconstruction. The added thickness created by the laminated and/or bondedsecured and folded fibers 12 at both ends of the device can be utilizedas a platform to create expanded drug delivery reservoirs for one ormore drugs at the distal and proximal end of the device, to providedirectional drug delivery as well as controlled drug release throughsurfaces of inner member and/or on the surfaces of the exterior of theouter member (e.g., the drug coating). The fiber ends 9 also provideincreased radial support at both ends of the device. The enlargedlateral ends 9 can result in a flared, expanded cross-section 111 asshown in FIG. 2B. When fully deployed, in some embodiments, the innerluminal diameter of the prosthesis is substantially consistent indiameter throughout its length and generally annular shaped, the outerdiameter of copolymer layer at the distal and/or proximal end of thedevice D2 at the expanded state is larger by 0.002 to 0.010 inches, or0.005 to 0.010 inches in some embodiments larger than the outer diameterat a midportion of the device D1, creating one or more drug deliveryreservoirs for one or more types of drugs. Alternatively, the drugdelivery element may be present not only at the ends but extendingpartially or completely over the prosthesis.

The stent 108 illustrated in FIG. 2A has in its unconstrained, expandedstate a first outer cross-sectional diameter D2 at each end and asecond, smaller cross-sectional diameter D1 at the central apex portionof the stent. The cross-sectional diameter of the stent preferablydecreases from one end to a central apex portion, and preferablyincreases from the central apex portion to the second end. The largercross-sectional diameter D2 at the ends relative to the central apexportion diameter D1 advantageously provides increased radial support forthe stent at the first and second ends. In some embodiments, the ratioof D2/D1 is at least about 1.005, 1.01, 1.02, 1.03, 1.04, 1.05, 1.07,1.10, 1.15, 1.20, 1.25, 1.30, or more.

In some embodiments, the prosthesis is selected to be oversized by atleast about 3%, 4%, 5%, 6%, 7%. 8%, 9%, 10%, or more than the diameterof the body lumen that the prosthesis is inserted into, or between about3% and 10% in some embodiments.

While the prosthesis 108 shown in FIG. 2A has a variable outer diameter,the prosthesis 108 preferably has relatively constant inner diameterthroughout its axial length to provide a stable flow path when theprosthesis is placed within a blood vessel.

FIG. 2C illustrates schematically an exploded view of a first tubularbody 2005 that may be made of a porous biocompatible material such asePTFE, PTFE, polyurethane, or similar materials. The second tubular body2010 comprises a helically wound and or braided polymer that canoptionally include a polyphosphoester or other drug coating 2020. Astent may be formed in some embodiments by annealing (e.g., on amandrel) the first 2005 and second 2010 tubular bodies. The firsttubular body 2005 preferably has a smaller diameter than the secondtubular body 2010 such that the first tubular body 2005 becomes theinner layer and the second tubular body 2010 becomes the intermediate orouter layer. In some embodiments, a third tubular body 2020 comprising adrug delivery layer may also be present and can be annealed to thesecond tubular body 2010, or applied on via a coating, spraying ordipping process to form a tri-layer stent.

Biodegradable Layer

The biodegradable intermediate layer may include a biodegradablepolymeric material, such as described in U.S. Patent Publication No.2006/0129222 A1 to Stinson, hereby incorporated by reference in itsentirety.

In some embodiments, a blended combination of polymer such asDLPLA-poly(di-lactide) can be utilized. DLPLA is an amorphous polymerexhibiting a random distribution of both isomeric forms of lactic acid,and accordingly is unable to arrange into an organized crystallinestructure. This material has lower tensile strength, higher elongation,and a much more rapid degradation time, making it more attractive as adrug delivery system. Poly(l-lactide) is about 37% crystalline, with amelting point of 170-180° C. and a glass-transition temperature of60-69° C. The degradation time of LPLA is much slower than that ofDLPLA, requiring more than 2 years to be completely absorbed. Copolymersof l-lactide and dl-lactide have been prepared to disrupt thecrystallinity of 1-lactide and accelerate the degradation process.

PGA-polyglycolide is the simplest linear aliphatic polyester. PGA wasused to develop the first total synthetic absorbable suture, marketed asDexon in the 1960s by Davis and Geck Inc. (Danbury, Conn.) Glycolidemonomer is synthesized from the dimerization of glycolic acid.Ring-opening polymerization yields high-molecular-weight materials, withapproximately 1-3% residual monomer present PGA is highly crystalline(45-55%), with a high melting point (200-225° C., such as 200-210° C.)and a glass-transition temperature of 35-40° C. Because of its highdegree of crystallization, it is not soluble in most organic solvents;the exceptions are highly fluorinated organics such ashexafluoroisopropanol. Fibers from PGA exhibit high strength and modulusand are too stiff to be used as sutures except in the form of braidedmaterial. Sutures of PGA lose about 50% of their strength after 2 weeksand 100% at 4 weeks, and are completely absorbed in 4-6 months.Glycolide has been copolymerized with other monomers to reduce thestiffness of the resulting fibers.

Lactide is the cyclic dimer of lactic acid that exists as two opticalisomers, d and l. l-lactide is the naturally occurring isomer, anddl-lactide is the synthetic blend of d-lactide and l-lactide. Thehomopolymer of l-lactide (LPLA) is a semi crystalline polymer. Thesetypes of materials exhibit high tensile strength and low elongation, andconsequently have a high modulus that makes them more suitable forload-bearing applications such as in orthopedic fixation and sutures.Poly(dl-lactide) (DLPLA) is an amorphous polymer exhibiting a randomdistribution of both isomeric forms of lactic acid, and accordingly isunable to arrange into an organized crystalline structure. This materialhas lower tensile strength, higher elongation, and a much more rapiddegradation time, making it more attractive as a drug delivery system.Poly(l-lactide) is about 37% crystalline, with a melting point of175-178° C. and a glass-transition temperature of 60-65° C. Thedegradation time of LPLA is much slower than that of DLPLA, requiringmore than 2 years to be completely absorbed. Copolymers of l-lactide anddl-lactide have been prepared to disrupt the crystalline of l-lactideand accelerate the degradation process.

Mechanical properties generally increase with increasing molecularweight. For instance, the strength and modulus of PLA generallyincreases with increasing molecular weight. Degradation time generallydecreases with decreasing initial molecular weight (i.e., a stent madeof a low molecular weight polymer would be bioabsorbed before a stentmade of a high molecular weight polymer). Low molecular weight PLA isgenerally more susceptible to thermo-oxidative degradation than highmolecular weight grades, so an optimum molecular weight range should beselected to balance properties, degradation time, and stability. Themolecular weight and mechanical properties of the material generallydecreases as degradation progresses. PLA generally has a degradationtime greater than 1 year. PLA has a glass transition temperature ofabout 60° C., so care must be taken not to store products inenvironments where high temperature exposure may result in dimensionaldistortion.

PLA, PLLA, PDLA and PGA include tensile strengths of from about 40thousands of pounds per square inch (psi) to about 120 psi; a tensilestrength of 80 psi is typical; and a preferred tensile strength of fromabout 60 psi to about 120 psi. Polydioxanone, polycaprolactone, andpolygluconate include tensile strengths of from about 15 psi to about 60psi; a tensile strength of 35 psi is typical; and a preferred tensilestrength of from about 25 psi to about 45 psi.

PLA, PLLA, PDLA and PGA include tensile modulus of from about 400,000pounds per square inch (psi) to about 2,000,000 psi; a tensile modulusof 900,000 psi is typical; and a preferred tensile modulus of from about700,000 psi to about 1,200,000 psi. Polydioxanone, polycaprolactone, andpolygluconate include tensile modulus of from about 200,000 psi to about700,000 psi; a tensile modulus of 450,000 psi is typical; and apreferred tensile modulus of from about 350,000 psi to about 550,000psi.

PLLA filament has a much lower tensile strength and tensile modulusthan, for example, Elgiloy® metal alloy wire which may be used to makebraided stents. The tensile strength of PLLA is about 22% of the tensilestrength of Elgiloy®. The tensile modulus of PLLA is about 3% of thetensile modulus of Elgiloy®. Stent mechanical properties andself-expansion are directly proportional to tensile modulus of thematerial. As a result, a PLLA filament braided stent made to the samedesign as the metal stent has low mechanical properties and would not befunctional. The invention advantageously provides polymeric braidedstents with radial strength similar to metal stents and the requiredmechanical properties capable of bracing open endoluminal strictures.

A bioabsorbable PLLA braided tubular stent changes size when constrainedonto a catheter delivery system and when deployed. A deployed PLLA stentis generally longer in length and smaller in diameter than a PLLA stentprior to loading. For example, PLLA stents that were initially 30 mmlong with external diameters of about 10.7 mm had deployed lengths ofabout 90 mm with diameters of about 6.3 mm.

Self-expanding stents can be formed from a number of resilient filamentswhich are helically wound and interwoven in a braided configuration. Thestents assume a substantially tubular form in their unloaded or expandedstate when they are not subjected to external forces. When subjected toinwardly directed radial forces the stents are forced into areduced-radius and extended-length loaded or compressed state. Thestents are generally characterized by a longitudinal shortening uponradial expansion.

In one preferred embodiment, the device is a stent which includes aplurality of elongate polylactide bioabsorbable polymer filaments,helically wound and interwoven in a braided configuration to form atube. Bioabsorbable implantable endoprostheses such as stents,stent-grafts, grafts, filters, occlusive devices, and valves may be madeof poly(alpha-hydroxy acid) such as poly-L-lactide (PLLA);poly-D-lactide (PDLA), polyglycolide (PGA), polydioxanone,polycaprolactone, polygluconate, polylactic acid-polyethylene oxidecopolymers, modified cellulose, collagen, poly(hydroxybutyrate),polyanhydride, polyphosphoester, poly(amino-acids), or relatedcopolymers materials, each of which have a characteristic degradationrate in the body. For example, PGA and polydioxanone are relativelyfast-bioabsorbing materials (weeks to months) and PLA andpolycaprolactone are a relatively slow-bioabsorbing material (months toyears).

A stent constructed of a bioabsorbable polymer provides certainadvantages relative to metal stents such as natural decomposition intonon-toxic chemical species over a period of time. Also, bioabsorbablepolymeric stents may be manufactured at relatively low manufacturingcosts since vacuum heat treatment and chemical cleaning commonly used inmetal stent manufacturing are not required. Furthermore, such stentscould be advantageous when two, three, or more stents are overlappedtogether in avoiding or reducing wear damage and crevice corrosion thatmay occur with overlapped metallic stents.

In comparison, a metal self-expanding stent generally has about the samedimensions before loading and after deployment. For metal stents, if itis known that the patient has a 9 mm diameter vessel, then a 10 mm metalstent (stent is intentionally oversized by about 1 mm) is loaded ontothe delivery system for implantation. This rule is not applicable for apolymer stent because more oversizing is necessary.

PLLA-Poly (L-lactic acid) fibers are processed by a two stepmelt-spinning method (extrusion and hot draw) from PLLA with threedifferent Viscosities—average molecular weight of approximately (494,000g/mol, 305,000 g/mol, and 262,000 g/mol). Before spinning, the polymerflakes are first milled into powders and dried under vacuum. Theextrusion die is operated at a temperature of 200° C.±30° C. In someembodiments, depending on the diameter of fiber utilized, up to38-spindle braiders/winders may be required for manufacturing.

The outer layer surface structure can vary from particle beads texturefor enhanced lodging to fibrous materials. The fiber manufacturingprocess in some embodiments includes a melt extrusion immediatelyfollowed by a drawing process to create a self-reinforced embodiment. Toattain maximum radial strength for the device the drawing of the moltenreferenced materials can occur, e.g., at an angle ranging from 60° to140° degrees. The isotropic polymer is transformed into a highlyanisotropic self-reinforced configuration. The self-reinforced fiber hasa high degree of molecular orientation in the direction of the long axisof the fiber. The vacuum dried material is extruded by an industrialgrade extruder having a 1.0 mm monofilament die. In the drawing process,the materials could be oriented with draw ratios of approximately 6.0 to10.0, corresponding to a final diameter of 0.029 mm in some embodiments.The self reinforced fibers are braided into a cylindrical/tubular shapeonto a 4-16 mm mandrel, the porous layer, or a cast using two verticallyoperating 24-spindle braiding/winding machines. Heat treatment takesplace in the vacuum oven at 120-160° C. for 7-25 minutes, or at up to200° C. for between 15-35 minutes in some embodiments. Next the stentsare left in at room temperature for approximately 15 to 25 minutes. Theviscosity-average molecular weight, in some embodiments, can beapproximately 220,000 g/mol after extrusion. The drawing processesdecrease the viscosity average weight to about 48,000 g/mol.

The mandrel's outer diameter, which may be from about 4 mm to about 11mm depending on the desired clinical application, can be larger than theouter diameter of the prosthesis by a factor of 15% to 25% to attain thefinal diameter post heat treating. In one embodiment, a 10 mm indiameter device would be fabricated/heat treated on a 12 mm OD mandrel.

The biodegradable polymer is preferably interwound radially to an innermembranous layer, and can be annealed together, in some embodiments, attemperatures ranging from 300 to 500 degrees Fahrenheit.

The biodegradable filament layer 201 can also be annealed on a mandrelor otherwise attached to the inner layer 200, as illustratedschematically in FIG. 1. Shown first is a first tubular body 200 then ahelically wound and braided polymer body 201. The multi-layered stentmay be formed in some embodiments by annealing layers 200 and 201. Thefirst tubular body 200 preferably has a smaller diameter than the secondtubular body 201 such that the first tubular body 200 becomes the innerlayer and the second tubular body 201 becomes the outer layer. One ormore drug release layers 202 may be present on one or more surfaces oflayers 200 and/or 201 as previously noted.

The prosthesis is preferably configured to be at least partiallybioresorbable and can in some embodiments, degrade in vivo over 1-3years. Heavy molecular weight polymers possess higher tensile strengthand would require additional time to intergrade to the vascular site.

One embodiment of a bioabsorbable polymeric layer 10 is illustratedgenerally in FIGS. 3 and 4. Biodegradable stent layer 10 is generallytubular and formed from two sets of oppositely-directed, parallel,spaced-apart and helically wound elongated strands or filaments 12. Thesets of filaments 12 are interwoven in an over and under braidedconfiguration intersecting at points such as 14 to form an open mesh orweave construction. As described in greater detail below, at least oneand preferably all filaments 12 are made of one or more commerciallyavailable grades of polylactide, poly-L-lactide (PLLA), poly-D-lactide(PDLA), polyglycolide (PGA), polydioxanone, polycaprolactone,polygluconate, polylactic acid-polyethylene oxide copolymers, modifiedcellulose, collagen, poly(hydroxybutyrate), polyanhydride,polyphosphoester; poly(amino acids), poly(alpha-hydroxy acid) or relatedcopolymers materials. Methods for fabricating stents 10 are generallyknown and disclosed, for example, in U.S. Pat. No. 4,655,771 to Wallstenand U.S. Pat. No. 5,061,275 to Wallsten et al., hereby incorporated byreference in their entirety.

Stent layer 10 is shown in its expanded or relaxed state in FIGS. 3 and4, i.e., in the configuration it assumes when subject to no externalloads or stresses. The filaments 12 are resilient, permitting the radialcompression of stent layer 10 into a reduced-radius, extended-lengthconfiguration or state suitable for delivery to the desired placement ortreatment site through a body vessel (i.e., transluminally). Stent layer10 is also self-expandable from the compressed state, and axiallyflexible.

Stated another way, stent layer 10 is a radially and axially flexibletubular body having a predetermined diameter that is variable underaxial movement of the ends of the body relative to each other. The stentlayer 10 is composed of a plurality of individually rigid but flexibleand elastic thread elements or filaments 12, each of which extends in ahelix configuration along a longitudinal center line of the body as acommon axis. The filaments 12 define a radially self-expanding body. Thebody may be provided by a first number of filaments 12 having a commondirection of winding but axially displaced relative to each other, andcrossing a second number of filaments 12 also axially displaced relativeto each other but having an opposite direction of winding.

The tubular and self-expandable body or structure formed by theinterwoven filaments 12 is a primary prosthetically-functional structureof stent layer 10. However, it is known that other structures andfeatures can be included in stents, and in particular features whichenhance or cooperate with the tubular and self-expandable structure orwhich facilitate the implantation of the structure. One example is theinclusion of radiopaque markers on the structure which are used tovisualize the position of the stent through fluoroscopy duringimplantation. Another example is the inclusion of a covering 15 oradditional interwoven filaments, for instance, to reduce the porosity oropen spaces in the structure so that the stent can be used to preventtissue in-growth or be used as a graft. Other examples includecollapsing threads or other structures to facilitate repositioning andremoval of the stent. Furthermore, many of the desirable features andproperties of stent layer 10 will be present if some, but not all, ofthe filaments 12 are made of a bioabsorbable polymeric material.

An implantable bioabsorbable stent layer 10 may be made by a preferredmethod of braiding such that 10-36 independent strands, such as 24, 30,or 36 strands for example, of 0.15-0.60 mm diameter bioabsorbablepolymeric filament are interwoven into helical shape strands on a roundbar mandrel of 3-30 mm diameter such that one-half of the number ofhelical strands are wound clockwise and one-half are woundcounterclockwise and such that each clockwise helical strand is adjacent(interbraided) to a counterclockwise strand, the tubular braid is madewith strand braid angles (angle between two filaments in thelongitudinal or axial direction) of 120-150 degrees (pitch angles, i.e.,the angle between a filament and transverse axis of the stent that maybe between about 15-45 degrees) while on the braid bar mandrel, thebraid is slid off of the braid bar and onto a 0.2-10 mm smaller diameterannealing bar or tube mandrel, each end of the braid pulled orcompressed to cause axial extension or compression of the braid on theanneal mandrel, or left free, and each end of the braid secured on eachend of the anneal mandrel to fix the preset axial position of the braid,or left free, annealing the braid on the anneal mandrel at a temperaturebetween the glass-transition temperature and melting temperature of thepolymer for 5-120 minutes in air, vacuum, or inert atmosphere, coolingthe annealed braid on the anneal mandrel to about room temperature,sliding the braid off of the anneal mandrel and cutting it to thedesired stent length. Another preferred embodiment includes at least onebioabsorbable-radiopaque marker strand.

Sterilization

The prostheses and delivery system components as described herein can besterilized by a variety of processes, including ethylene oxide (EtO)with a relatively short degassing cycle, radiation (gamma or e-beam) orheat (steam or dry) processes. Other relatively low temperatureprocesses that can be used include vaporized hydrogen peroxide, hydrogenperoxide gas plasma, or ozone.

A relatively new sterilization process relies on oxides of nitrogen, andprincipally, nitrogen dioxide. Such a process can be useful, forexample, for a combination device that includes a drug deliverycharacteristic. In the presence of oxygen (air), nitric oxide reacts toform reactive nitrogen species (RNS) including nitrogen dioxide (NO2)and, to a much lesser concentration, its dimer, dinitrogen tetroxide(N2O4). Other transient species may be present at low concentrations (<1ppm), including: nitrogen trioxide (NO3), dinitrogen trioxide (N2O3),dinitrogen pentoxide (N2O5), and nitrous oxide (N2O). In a sterilizationchamber where NO is mixed with air, most of the NO reacts to form NO2.The only other oxide of nitrogen that forms under these circumstancesand is stable at concentrations higher than 1 ppm is N2O4, which existsin equilibrium with NO2 and the concentration of which is determined bythe NO2 vapor pressure. If the air is humidified, NO2 can be convertedinto nitric acid (HONO2) at trace levels.

A recently developed sterilization process uses low concentrations (lessthan about 30, 25, 21, 20, 15, or less mg/L) of nitrogen dioxide gas inthe presence of air and water vapor. The process is typically deliveredat or near room temperature and consists of evacuation of air from thechamber, the introduction of the sterilant, and the addition ofhumidified air to a preset pressure, which is typically at or nearambient pressure. Depending on the physical design and packaging of thedevice to be sterilized, the sequence of: vacuum→sterilantinjection→humid air injection may be repeated several times or thesequence can be changed. At the nitrogen dioxide concentrations used,and considering the operating temperature and pressure of the process,the NO2 remains in the gas phase and acts as an ideal gas throughout thesterilization cycle.

It has been determined that in the gas sterilization process NO2 is thekey sterilizing agent. Other RNS may contribute in less-significantways. Although the literature cites many other potential reactions, thespecific environment established with the sterilization system limitsthe chemical species formed and the breadth of biological response. Thislimit allows the process to be focused and controlled.

Gas reactions that occur in the sterilization chamber are predictableand have been determined by calculation, computer modeling, andempirically. The sterilant gas concentration mixtures over time arepredictable. The reaction rates and resulting concentrations of NO2 andother oxides of nitrogen that result from the reaction of air and NOhave been calculated. The starting concentration was set at 0.1% NO inair. NO reacts with oxygen in the air to create NO2. The constant sum ofNO and NO2 indicates that these two molecules account for almost all ofthe nitrogen present. The calculations predict a rapid conversion of NOto NO2 with only trace amounts of N2O4 due to the low NO2 concentration.NO2 is an effective sterilant at low concentrations, often between 6 and12 mg/L, 8 and 10 mg/L and typically less than 21 mg/L, depending on theapplication. Therefore, relatively small containers of the NO2 arerequired.

FIG. 5 is a cross-sectional view of one of the polymeric filaments 12.As shown, the filaments 12 may be substantially circular in crosssection, although other configurations such as oval or rectangular(ribbon) may be used.

In some embodiments, the polymeric filament intermediate layer describedabove can be operably attached, such as radially interwound to abiocompatible inner tubular membrane layer. The membrane is preferably asynthetic material such as, for example, a thermoplastic such as ePTFE,Teflon, polyethylene, or polyurethane. In some embodiments, the membraneand the polymeric filaments may be annealed together, such as, forexample, at a temperature ranging from about 300° F. to about 500° F.This layer can be the inner lumen layer, although it could also be anouter layer, or both an inner and outer layer to promote cellularin-growth.

In some embodiments, a lumen layer, such as an inner or outer layerincludes a porous media feature network of open-celled directional poresfor enhanced fluid dynamics. In some embodiments, the pore size may beconstant throughout the membranous layer. The prosthesis may also beprepared with different mean pore sizes. Pore size can be an importantparameter in that certain macromolecular drugs may be excluded from usewhere the pore size is very small. The pore size may also play a role indetermining the extent of cellular infiltration or tissue in-growthduring implantation of the stent. While cellular in-growth is sometimesdesirable, it can also lead to complications such as infection anddifficulty in removing the stent. Stents with a mean pore size ofgreater than about 10 microns can allow infiltration of cellular sizedbiomaterials; stents with mean pore sizes in the range of 1-10 micronsmay accommodate infiltration of some of the above bio-materials. Stentswith pore sizes less than about 1 micron will not generally accommodateinfiltration of any of the above biomaterials but can accommodateinfiltration of macromolecular and small biomaterials. Thus, the poresize of the stent may be varied to foster or inhibit cellularinfiltration and/or tissue in-growth. Of course, the pore size may alsobe varied to facilitate delivery of drugs of different molecular sizes.Furthermore, the pore size and overall porosity of the membrane layercan be predetermined for a particular clinical application in order tocontrol the mass loss as well as drug elution, and thus the degradationrate of the stent, caused, for example, by high velocity blood flowthrough the stent. In some embodiments, the porous membrane layer can beconfigured such that the stent maintains at least about 50% of itsradial strength for a period of at least 3 months, 6 months, 9 months,12 months, 18 months, 2 years, 3 years, 4 years, 5 years, 7 years, 10years, or more.

Optionally present in one or more of the layers are radiopaque markerelements to improve visualization of the stent, for example, underfluoroscopy. Also the delivery system/catheter may possess radiopaquemarkers defining the distal and proximal end of the vascular prosthesiswhile in the delivery system. The flexible nature and reduced radius ofthe compressed prosthesis enables it to be delivered through relativelysmall and curved vessels in percutaneous transluminal angioplasty. Insome embodiments, the marker elements can either be located directlyadjacent the ends of the stent in a manner only slightly increasing alength of the stent or the marker elements can be spaced from theadjacent portions of the stent in a manner causing the marker elementsto enhance somewhat the overall length of the stent. With the radiopaquemarker elements in place attached to the ends of the stent, the locationand orientation of the stent can be precisely determined both before,during, and after implantation and radial expansion of the stent withinthe body lumen. In some embodiments, the radioopaque marker elements aremade of a metal or a metal alloy, such as, for example, one or more ofnitinol, Elgiloy®, Phynox®, MP35N, stainless steel, nickel, titanium,gold, rhenium, tungsten, palladium, rhodium, tantalum, silver,ruthenium, and hafnium. The marker element could be a 90% platinum and10% iridium alloy in one particular embodiment.

FIG. 6 illustrates a schematic cut-away view of a portion of the wall ofa stent 100 that may be as in FIG. 1 with an inner layer comprising aplurality of bioabsorbable polymer filaments 14. In some embodiments,the filaments 14 are radially interwound with ePTFE, nylon,polypropylene, or another biocompatible material. The stent 100 alsocomprises an outer layer 102 with a controlled-mass release and/or drugrelease element, such as, for example, polyphosphoester microspheres.The outer layer 102 may be, in some embodiments, spray-dipped, coated,annealed, bound covalently or noncovalently to the inner layer. Thus,the outer layer may be a tubular layer as illustrated in FIGS. 1 and 2 cor it may be a layer of coating surrounding a portion or all of theindividual fibers in the intermediate woven layer as shown in FIG. 6.

FIG. 7 illustrates schematically a cross-section through a stent,according to one embodiment of the invention. The cross-sectional shape204 of the stent may be non-circular, and may be acorn-shaped as shown.While the device is inserted/loaded in the delivery system, theconstructed embodiment tends to take a set shape, this conditiondirectly relates to the delivery system OD size, and the stent foldingmethods in the delivery system/catheter as described below. Once thesheath of the delivery system/catheter is pulled back in a proximaldirection and the device is released at the target site the device thentransforms into a round and circular shape through flow through theinner lumen. Initially it may create a better lodging condition once thedevice has intergraded in the vascular site it would contour to thespecific shape of the body lumen.

FIGS. 8-11 illustrates several non-limiting examples of theself-expandable stent in a compressed configuration. The compressedshape may be, for example, U-shaped 400 as shown in FIG. 8, W-shaped 402as shown in FIG. 9, “carpet rolled” 404 as shown in FIG. 10, or“starburst” radially compressed shape 406 as shown in FIG. 11. One ofordinary skill in the art will appreciate that many other compressedprosthesis configurations are possible that do not necessarily have tobe compressed radially inwardly.

The prosthesis of the present invention can be implanted in variouslocations. In addition to the large coronary vessels such as the leftmain, circumflex, left anterior descending, or right coronary artery,the stent may advantageously be placed in the smaller branches of thecoronary arteries, such as the diagonals, marginals or posteriordescending artery, or various peripheral vessels such as the ascendingor descending aorta, internal mammary, brachial, femoral, carotid, orCircle of Willis cerebral vessels. The stent is also particularlyadvantageous for curved and tortuous vessels, some of which arementioned above. The specific features includes but not limited to selfexpanding design, diameters and length specifications, and drug deliveryreservoirs. The prosthesis may also be placed in veins such as theinternal or external jugular vein, superior or inferior vena cava,femoral vein, or great saphenous vein, and non-vascular lumens such asthe biliary tree, esophagus, intestines, ureters, urethra, trachea,bronchi, fallopian tubes and the like.

In some embodiments, a peripheral (non-coronary) stent may have a lengthof between 5-20 cm, a wall thickness of 0.009 of an inch to 0.015 of aninch, a compressed outside diameter of 7 French to 15 French and anunfolded outside diameter of 4 cm to 11 cm. For coronary applications,the end device may possess the following parameters in certainembodiments: 2-5 mm outer diameter; 10-40 mm length; 0.004-0.007 inchwall thickness.

FIG. 11A illustrates an embodiment of a stent 1000 that can be asdescribed previously, with a proximal end 500, distal end 502, andadditionally one, two, or more side orifices 504 disposed within thesidewall of the stent 1000. In some embodiments, a stent 1000 can haveat least 2, 3, 4, 5, 6, 7, 8, 9, 10, or more side orifices 504. The sideorifices 504 can be advantageously dimensioned to, for example, promoteblood flow to side-branch arteries that may otherwise be blocked orlimited by a stent placed across a main vessel. Some non-limitingexamples of side-branch vessels can include, for example, the acutemarginal, posterior descending artery, obtuse marginal, septalperforators, and diagonal arteries of the coronary arterial circulation.

If a plurality of side orifices 504 are present, they can each bealigned in a number of ways depending on a particular patient's vascularanatomy and the desired clinical result. In some embodiments, the sideorifices 504 can be arranged along an axis parallel to the longitudinalaxis of the stent 1000 as shown in FIG. 11A or longitudinally offsetfrom each other as shown in FIG. 11B. FIG. 11C illustrates a stent 1000as described and illustrated above and disposed within a lumen of a mainvessel 516. As illustrates a first side orifice 504 is sized to promoteblood flow to a first side branch vessel 518, and a second side orifice504′ is sized to promote blood flow to a second side branch vessel 520.In some embodiments, the side orifices 504 in total can make up atbetween about 1% and 80% of the total surface area of the outsidediameter of the stent, such as between about 5% and 60%, or betweenabout 31% to 61% in some embodiments. In some embodiments, a side branchorifice 504 may have a diameter of between about 1 mm and about 5 mm. Insome embodiments, one or more therapeutic agents as described elsewhereherein can be concentrated around side orifices 504 to better preventthrombosis or stenosis across the side orifices 504.

In some embodiments, a stent can include one or more radially enlargedends similar to that described in connection with FIG. 2A above, thatcan be formed by folding one or more layers of the stent back over oneor both of the proximal end and/or the distal end of the stent. Theenlarged, folded ends can then be secured by a variety of methods, suchas, for example, suturing, adhesives, annealing, or the like as will bedescribed in greater detail below. The stent can include one, two,three, or more layers as previously described. As illustrated in FIG.11D, in one embodiment, a stent 1000 has a proximal end 500 and a distalend 502 and includes a braided layer 2010 and a porous membrane layer2005 that can be as previously described. An optional drug deliverycharacteristic described elsewhere in the application is not shown forclarity. As illustrated, one or more segments 550 of the porous membranelayer 2005 at the proximal end 500 of the stent 1000 is folded over thebraided layer 2010. In some embodiments, the folded segment 550 can havea length from about 0.01 inches to about 0.10 inches, such as from about0.30 inches to about 0.50 inches, or about 0.40 inches in otherembodiments. FIG. 11E illustrates another embodiment of a folded stentend with the porous membrane layer 2005 being the outer layer relativeto the braided layer 2010 and having a portion 550 folded over itself.FIG. 11F illustrates yet another embodiment where a segment 550 of boththe membrane layer 2005 and the braided layer 2010 are folded overthemselves.

FIG. 11G illustrates a perspective view of a stent 1000 with radiallyenlarged proximal 500 and distal 502 ends resulting from folding over ofone, two, or more layers as previously described.

FIG. 11H schematically illustrates an end of a stent with a foldedportion 550 as previously described. The membrane layer 2005 and thebraided layer 2010 can be attached mechanically by suturing the twolayers 2005, 2010 together using any appropriate suture material, suchas, for example, a suture made of a biodegradable material disclosedelsewhere in the application, catgut, PTFE, ePTFE, polyester,polyglycolic acid, poliglecaprone, nylon, polyethylene, polypropylene,or polyurethane, depending on the desired clinical result. The suturescould be, for example, simple interrupted sutures or continuous runningsutures. As illustrated in FIG. 11H, tied suture loops 552 areillustrated attaching the membrane layer 2005 and the braided layer 2010together over the folded portion 550 of the stent. The sutures 552 canbe tied in a plane generally perpendicular to the longitudinal axis ofthe stent as illustrated in FIG. 11H, in a zig-zag pattern in anotherembodiment as illustrated in FIG. 11I, or in other patterns as known inthe art. In other embodiments, the sutures 552 are also attached in anarea of the stent where there is no folded over portion (e.g., towardthe midpoint of the stent). Any number of suture loops can be utilized,such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more. The sutures 552 could beattached to the stent near the proximal end, distal end, or both. Inother embodiments, other attachment techniques such as an adhesive,e.g., fibrin glue can be used to attach two or more stent layerstogether. In some embodiments, one or more ends of the stent could beheat-treated as described above to enhance attachment of the layerstogether, for example. By overlapping the thin layer of syntheticmembrane over the braided structure, it is possible to conceal andsecure the radiopaque markers, such as between two layers of a fold, andavoid undesirable marker detachment and migration into the bloodstream.The overlapping of the thin layer of membrane could also provide abetter radial support and better fluid dynamics at one or both ends ofthe device.

FIG. 11J illustrates a perspective view of a stent having a layer ofinterwound biodegradable filaments 2010, according to one embodiment ofthe invention. The stent can include one, two or more radioopaque markerelements 11, such as near the proximal or distal ends of the stent asillustrated. FIG. 11K is a cross-section of the stent of FIG. 11Jthrough line 11K-11K of FIG. 11J. The stent could also have additionallayers as described elsewhere in the application, including thefollowing embodiments.

FIG. 11L illustrates a perspective view of a stent having an outerbraided layer 2010 and an inner membrane layer 2005 with a foldedportion 550 of the inner membrane layer 2005 over the braided layer 2010as previously described. As illustrated, the layers 2005, 2010 areattached together using sutures 552, such as near both the proximal 500and distal 502 ends as shown. The stent can also include one or moreradioopaque marker elements 11, such as at least 1, 2, 3, 4, or moremarker elements 11 disposed near either the proximal end 500 and/or thedistal end 502 of the stent, although other alternative or additionallocations, such as near or at the midpoint of the stent are also withinthe scope of the invention. In some embodiments as shown, theradioopaque marker element is mechanically secured in between thebraided layer 2010 and the folded portion 550 of the membrane layer2005. However, the marker could also be placed in between the braidedlayer 2010 and membrane layer 2005 in embodiments where no foldedportion 550 is present. The radioopaque markers 550 can bioincorporatein the luminal wall and remain visible under fluoroscopy followingbiodegradation of the stent. The marker element 11 could be either solidor hollow, and any appropriate shape, such as circular, cylindrical,triangular, or rectangular. In some embodiments, the marker element iscylindrical and hollow with a length of between about 0.01 inches toabout 0.1 inches, such as about 0.035 inches. In some embodiments, themarker element 11 could have an inner diameter of between about 0.005inches to about 0.020 inches, such as between about 0.0095 inches andabout 0.0145 inches. In some embodiments, the marker element 11 couldhave a wall thickness of between about 0.001 inches to about 0.005inches, such as between about 0.0015 inches and about 0.0025 inches.

In some embodiments for coronary applications, the stent could have anouter diameter of from about 1 mm to 4.5 mm in some embodiments. Inperipheral applications, the stent could have an outer diameter of fromabout 5 mm to 15 mm, or about 7 mm in some embodiments. The stent couldhave a constrained outer diameter during delivery of from about 1.5 mmto about 5.5 mm, such as about 3.5 mm in some embodiments. The stentcould have a length of the overlapped folded portion to be between about0.030 to 0.060 inches, or between about 0.030 and 0.040 inches in someembodiments, and a total length of about 2-20 cm, or about 10 cm in someembodiments.

FIG. 11M illustrates a perspective view of a stent similar to FIG. 11L,except that the membrane layer 2005 is the outer layer with respect tothe braided layer 2010. At least one of the layers, such as the membranelayer 2005 can have a folded-over portion 550 to secure the markerelements 11 and have suture loops 552 or other attachment means aspreviously described. A cross-section through lines 11N-11N of the stentis illustrated in FIG. 11N.

FIG. 110 illustrates a perspective view of a braided layer 2010 of ahybrid stent made up of interwoven strands of both bioabsorbable fibers14 as previously described as well as nonbioabsorbable fibers, such asmetallic strands 15. The metallic strands 15 can include materials, suchas, for example, nitinol, Elgiloy®, Phynox®, MP35N, stainless steel, oranother metal or alloy. In one embodiment, the stent includes 24 stands,18 made of a bioabsorbable material such as PLA, and 6 strands made of ametallic material. However, any number of bioabsorbable andnonbioabsorbable could be used for stent construction, as previouslydescribed, such as, for example, 36 strands, of which 27 arebioabsorbable and 9 metallic. In other embodiments, between about 4% and96%, such as between about 16% and 84%, 16% and 50%, or about 25% of thestrands are made of a metallic material. In some embodiments, less thanabout 70%, 60%, 50%, 40%, 30%, 20%, 10%, or less of the strands are madeof a metallic material. The metallic strands 15 could be interspersedwith the bioabsorbable fibers 14 at regular intervals throughout thebraid, such as every other, 3^(rd), 4^(th), 5^(th), 6^(th), 7^(th),8^(th), 9^(th), or more strand being a metallic strand 15, orinterspersed irregularly depending on the desired clinical result. Thestent could also optionally include have an inner and/or outer membranelayer 2005 (not shown), and also a drug delivery characteristic aspreviously described. A cross-section through lines 11P-11P of the stentis illustrated in FIG. 11O. A hybrid bioabsorbable-metallic stent couldadvantageously result in a reduced loss of radial strength over a periodof time. Late recoil (negative remodeling) is one of the most importantcauses of restenosis following bioabsorbable stent implantation. As thevessel heals, the artery tends to shrink. Due to their intrinsic highradial force, metallic stents maintain the scaffolding effect over time,thus preventing this phenomenon. To the contrary, pure bioabsorbablescaffoldings lose radial strength relatively quickly allowing the arteryto recoil more rapidly. By combining a metallic scaffolding with abioabsorbable material one could advantageously maintain an appropriateradial force over time allowing the absorption process to take place,avoiding negative remodeling. In some embodiments, the residual metalliccomponent could be a small fraction of what is seen today with balloonexpandable metallic stents. This design could advantageously obviate theneed for radiopaque markers as the metallic component is visible underfluoroscopy.

Delivery Systems

FIGS. 12-19 illustrate various delivery devices and methods that may beused with the prosthesis shown.

FIGS. 12-14 are illustrations of a coaxial inner/outer tube catheterdelivery device 2000 for delivering a stent 1000 to a treatment site ina body vessel. An extension 45 extends from side port 41 to an opening42.

As shown, stent 1000 may be carried by the distal portion of deliverydevice 20, and is placed on the delivery device in a radially contractedor compressed state, such as, for example, illustrated in FIGS. 8-11.The proximal portion of delivery device 2000 generally remains outsideof the body for manipulation by the operator.

The manner by which delivery device 2000 is operated to deliver stent1000 to a treatment site in a body vessel or lumen including curvedsections is illustrated in FIGS. 15-18. As shown, stent 1000 is placedin a radially compressed state in a surrounding relationship to theouter distal end of inner tube 30. A tip 31 is disposed at the distalend of tube 30. Stent 1000 is constrained on inner tube 30 by thedouble-walled section of coaxially designed delivery system 55. It isimportant that stent 1000 not be confined too tightly on inner tube 30.Coaxially designed delivery system 55 should apply just enough force tostent 1000 to hold stent 1000 in place. The double-walled section ofcoaxially designed delivery system 55 can be removed from around stent1000 by pulling valve body 40 (see FIG. 12) and proximal tube 50 in aproximal direction. The double-walled section “rolls” off stent 1000. Nosliding movements take place between stent 1000 and inner wall 56 (FIG.14) which contacts stent 1000. Opening 59 are located in the double wallsection of the opening 55. Along with the movement of the double-walledsection in a proximal direction, the distal end of stent 1000 will beexposed in a radial direction to engagement against the wall of the bodyvessel. As the double-walled section of the outer member of thecoaxially designed delivery system 55 continues moving proximally, moreof stent 1000 expands in a radial direction until the entire length ofstent 1000 is exposed and engages the wall of a body vessel.

Lumen 35 (FIG. 14) is used to enable delivery device 2000 (FIG. 12) tofollow a guide wire (not shown) previously inserted percutaneously intothe body vessel. The lumen of inner tube 30 can also be used tointroduce a contrast fluid to the area around the distal end of deliverydevice 2000 so the position of delivery device 2000 can be detected(e.g., through the use of fluoroscopy or X-ray techniques).

The stents of the present invention may be delivered by alternativemethods or using alternative devices. For instance, the device describedin Heyn et al., U.S. Pat. No. 5,201,757 may be utilized, which isincorporated by reference in its entirety herein.

FIG. 19 illustrates a delivery device with an outer tube 61 includingmember 63 and an inner tube 62 including members 64, 65. Stent 1000 maybe inserted in a collapsed state in region 66, and one position ofmember 65 is shown at about region 67. Member 64 may move in thedirection of arrow 68 to push the stent out through end 70 into contactwith the interior of wall 72. The stent 1000 is shown as lines 69, 71.The end 70 may be moved by moving member 63 in the direction of arrow73.

FIG. 20 is a schematic angled perspective view of a stent 402 foldedinto a “W”-like shape within a delivery catheter 1002. Pusher element1004 may be used to deploy stent 402 into a desired location in the bodylumen, where it can assume its expanded configuration. As describedabove, the stent 402 with enlarged lateral ends may reduce the risk ofundesirable stent migration.

FIG. 21A illustrates a schematic view of an alternative coaxial stentdelivery system, according to one embodiment of the invention. The stentdelivery system 300 includes an inner tube 310 having a proximal end anda distal end 312, and an outer tube 320 having a proximal end and adistal end 322 configured to slide coaxially over the inner tube 310. Aradioopaque marker 11 as previously described can be positioned at ornear the distal end 322 of the outer tube 320 as illustrated. In someembodiments, a radioopaque marker 11 can also be placed at or near thedistal end 312 of the inner tube 310 as well. In such embodiments with amarker 11 on both the inner tube 310 and the outer tube 320, movement,such as proximal retraction of the inner tube 310 by a distance greaterthan the length of the stent can serve as an indicator that the stentshould expand and be deployed in the desired vessel. Also shown is aproximal Luer port 330 adapted to house a guidewire (not shown)therethrough and/or for infusion or aspiration of fluid, medication, orthe like via the inner tube 310 lumen. The proximal end of the outertube 320 includes a proximal adapter 360 connected via tubing 350 to acheck valve 340 for infusion or aspiration of fluid, medication, or thelike via the outer tube 320 lumen. In some embodiments, the deliverysystem can include one, two, or more balloon expansion elements that caneach have differing shapes, pressures, and volumes, that can be useful,for example, for “touch-up” procedures. Furthermore, the delivery systemcan include treating the stent or any other delivery system componentswith heat or other energy sources for in situ curing and/or molding ofthe materials.

As described above, a self-expanding stent can be crimped on to innertube 310 and prevented from expanding during delivery by the presence ofthe coaxially arranged outer tube 320. The distal end of the deliverysystem 300 can then deployed to the desired location in the body over aguidewire, for example, a stenosis in a coronary artery. The marker 11on the distal end 322 of the outer tube 320 can be utilized tofacilitate proper positioning. Relative movement of outer tube 320 withrespect to inner tube 310, such as in a proximal direction will allowthe stent to self-expand.

FIG. 21B is a schematic view of the outer tube 320 with components aspreviously described. In some embodiments, the outer tube can have aninner diameter from about 0.15 inches to about 0.20 inches, such asabout 0.165 inches, and outer diameter from about 0.16 inches to about0.21 inches, such as about 0.18 inches, a wall thickness of betweenabout 0.005 to 0.002 inches, such as about 0.01 inches, and a length ofbetween about 20 and 40 inches, such as about 27 inches in someembodiments.

FIG. 21C is a schematic view of the inner tube 310 with components aspreviously described, also including hypotube 370 within inner tube 310.

Multi-Stent Delivery System

In some embodiments, multiple stents, such as at least 2, 3, 4, 5, ormore stents can be delivered during a single procedure using amulti-stent delivery system, such as, for example, described andillustrated in FIGS. 1-8G and paragraphs [0008] to [0059] of U.S. Pat.Pub. No. 2008/0234799 to Acosta et al. and FIGS. 1-10 and paragraphs[0015] to [0070] of U.S. Pat. Pub. No. 2008/0255653 to Schkolnik, bothof which are hereby incorporated by reference in their entireties. Insome embodiments, each stent can be placed approximately 3-10 mm, suchas about 5 mm apart on the delivery catheter. In some embodiments, thedelivery system includes a detachment mechanism, such as a cuttingelement such that a single stent can be cut into several shortersegments using the same delivery system. The delivery system can alsoinclude radiopaque marker elements between each stent to furtherfacilitate delivery under fluoroscopy.

While this invention has been particularly shown and described withreferences to embodiments thereof, it will be understood by thoseskilled in the art that various changes in form and details may be madetherein without departing from the scope of the invention. For all ofthe embodiments described above, the steps of the methods need not beperformed sequentially and the individual components of the devices maybe combined permanently or be designed for removable attachment at theclinical site. Additionally, the skilled artisan will recognize that anyof the above-described methods can be carried out using any appropriateapparatus. Further, the disclosure herein of any particular feature inconnection with an embodiment can be used in all other disclosedembodiments set forth herein. Thus, it is intended that the scope of thepresent invention herein disclosed should not be limited by theparticular disclosed embodiments described above.

1. An intraluminal prosthesis, comprising: a first end, a second end,and an elongate tubular body with a lumen therethrough; a first layercomprising flexible interbraided filaments, wherein a first group offilaments comprise a biodegradable material, wherein the prosthesis hasa first cross-sectional outer diameter at the first end, a secondcross-sectional outer diameter at the second end, and a thirdcross-sectional outer diameter at a mid-point on the prosthesis axiallydisplaced from the first end and the second end of the prosthesis,wherein the prosthesis is configured such that the first end and thesecond end both comprise a first wall, wherein a portion of the firstwall is folded over to form a second wall, wherein the second wall issecured to the first wall, wherein the first cross-sectional outerdiameter and the second cross-sectional outer diameter are both largerthan the third cross-sectional outer diameter when the prosthesis is ina first, radially compressed configuration for delivery as well as whenthe prosthesis is in a second, radially enlarged configuration within ablood vessel, wherein the prosthesis has a continuous, cylindricalcross-sectional inner diameter throughout its axial length, wherein theprosthesis comprises a bioactive agent delivery reservoir between thefirst wall and the second wall.
 2. The prosthesis of claim 1, furthercomprising a second group of filaments, wherein the second group offilaments comprises a metallic material.
 3. The prosthesis of claim 2,wherein the first group of filaments comprising a biodegradable materialmake up 70% or more of the total number of filaments and the secondgroup of filaments make up 30% or less of the total number of filaments.4. The prosthesis of claim 1, wherein the bioactive agent reservoircomprises a drug.
 5. The prosthesis of claim 4, wherein the drug isselected from the group consisting of: paclitaxel, rapamycin,zotarolimus, and tacrolimus.
 6. The prosthesis of claim 1, wherein thefirst bioactive agent comprises a stem cell.
 7. The prosthesis of claim1, wherein the second wall is secured to the first wall with sutures. 8.The prosthesis of claim 1, wherein the second wall is bonded to thefirst wall.
 9. The prosthesis of claim 1, further comprising at leastone side orifice along the elongate tubular body.
 10. The prosthesis ofclaim 1, further comprising at least one radiopaque marker securedbetween the first wall and the second wall.
 11. The prosthesis of claim1, further comprising a second layer, wherein the second layer comprisesa porous material.
 12. The prosthesis of claim 11, wherein the secondlayer is the outer layer relative to the first layer.
 13. The prosthesisof claim 11, wherein the second layer is the inner layer relative to thefirst layer.
 14. An intraluminal prosthesis, comprising: a first end, asecond end, and an elongate tubular body with a lumen therethrough; afirst layer comprising flexible biodegradable interbraided filaments,wherein the prosthesis has a first cross-sectional outer diameter at thefirst end, a second cross-sectional outer diameter at the second end,and a third cross-sectional outer diameter at a point on the prosthesisaxially displaced from the first end and the second end of theprosthesis, wherein the prosthesis is configured such that the first endand the second end both comprise a first wall, wherein a portion of thefirst wall is folded over to form a second wall, wherein the second wallis secured to the first wall, wherein the first cross-sectional outerdiameter and the second cross-sectional outer diameter are both largerthan the third cross-sectional outer diameter when the prosthesis is ina first, radially compressed configuration for delivery as well as whenthe prosthesis is in a second, radially enlarged configuration within ablood vessel, wherein the prosthesis has a continuous, cylindricalcross-sectional inner diameter throughout its axial length, wherein theprosthesis comprises a bioactive agent between the first wall and thesecond wall.
 15. An intraluminal prosthesis, comprising: a first end, asecond end, and an elongate tubular body with a lumen therethrough; afirst layer comprising flexible biodegradable interbraided filaments;and a second layer comprising a bioactive agent; wherein the prosthesishas a first cross-sectional outer diameter at the first end, a secondcross-sectional outer diameter at the second end, and a thirdcross-sectional outer diameter at a mid-point on the prosthesis axiallydisplaced from the first end and the second end of the prosthesis,wherein the prosthesis is configured such that the first end and thesecond end both comprise a first wall, wherein a portion of the firstwall is folded over to form a second wall, wherein the second wall issecured to the first wall, wherein the first cross-sectional outerdiameter and the second cross-sectional outer diameter are both largerthan the third cross-sectional outer diameter when the prosthesis is ina first, radially compressed configuration for delivery as well as whenthe prosthesis is in a second, radially enlarged configuration within ablood vessel, wherein the prosthesis has a continuous, cylindricalcross-sectional inner diameter throughout its axial length, wherein theprosthesis comprises a reservoir of the bioactive agent and at least oneradiopaque marker element between the first wall and the second wall.16. The prosthesis of claim 15, wherein the first cross-sectional outerdiameter is at least about 1.0× of the third cross-sectional outerdiameter.
 17. The prosthesis of claim 15, wherein the firstcross-sectional outer diameter is at least about 1.02× of the thirdcross-sectional outer diameter.
 18. The prosthesis of claim 15, whereinthe first cross-sectional outer diameter is at least about 1.05× of thethird cross-sectional outer diameter.
 19. The prosthesis of claim 15,wherein the bioactive agent comprises a stem cell.
 20. The prosthesis ofclaim 15, wherein the bioactive agent comprises a drug.
 21. Theprosthesis of claim 15, wherein the drug prevents restenosis.
 22. Theprosthesis of claim 15, wherein the second layer is spray-dipped on thefirst layer.
 23. The prosthesis of claim 15, wherein the second layer isannealed to the first layer.
 24. The prosthesis of claim 15, wherein thesecond layer is covalently bound to the first layer.
 25. The prosthesisof claim 15, wherein the second layer is non-covalently bound to thefirst layer.